Disclaimer

The information contained in these pages is not meant to be taken as an endorsement of any medical approach, procedure, or treatment of any kind. If you have symptoms, seek immediate professional medical attention. The topics here are presented solely as potential options to be discussed with your medical professional.

It was determined that only 11 out of the 1672 studies fit the criteria of a randomized, controlled clinical trial. A total of 3701 patient histories were examined using recurrence as an end point. It was determined that of the drugs: Thiotepa, Epirubicin, Mitomycin C and Mitoxantrone - Mitomycin C was the most effective. A single instillation can delay recurrence at 1 year by 30%, multiple instillations by 31% after 2 years.

Chemo vs BCGIn another meta-analysis, from 97 citations, 9 fit the required criteria [Huncharek M., 2003]: Randomized controlled clinical trials comparing intravesical chemotherapy to BCG, with a minimum of 2 years follow up and more than 20 patients per arm. A total of 2261 cases were examined; the conclusions were:
--There is little advantage of BCG over intravesical chemotherapy, about 11%
--The currently perceived superiority of BCG may be an artifact since most randomized trials include chemotherapy failures.
--47% of people who fail intravesical chemotherapy respond to BCG as second line treatment.

Chemo vs BCG on Carcinoma in situA meta-analysis of randomized controlled trials with the inclusion criteria of primary, secondary or concurrent CIS was performed [Silvester R., 2005], From a total of 14 citations, 9 fit the criteria and 700 cases were examined. It was concluded that BCG had a superior effect on disease-free status, but no clear conclusions can yet be drawn regarding the impact of BCG on long term survival.

Problems with published dataThe number of trials that fit criteria must be standardized
The number of patients included is not high enough to draw concrete conclusions
The follow-up lenghts vary
There are different treatment protocols used
No distinction is made between primary, secondary or recurrent CIS

While meta-analysis does support important information, more questions remain to be answered via properly designed and adequately powered randomized trials

Is there a solution?Critical evaluation must lead to innovation and standardization regarding terminology, treatment strategies and methodology/end points.

What we can say about superficial bladder cancer is that it's a peculiar disease known for:
-high incidence of recurrences
-negligible incidence of progression (>T2)
-relevant role of endoscopic treatment/management and intravesical therapy
-the limited role of imaging tools

The main questions that remain open are:
--who is the optimal candidate
--what's the best drug? How does it work?
--what's the optimal regimen- best time for beginning treatment?
--how long should the drug be kept in the bladder?
--what is the ideal interval between instillations?
--what dose should be given at each instillation?
--how long should the drug be administered? Maintenance, no maintenance?
--in what liquid and what volume should it be dissolved?
--will all tumor respond to the treatment?
--what's theinfluences of diuresis, urinary pH, concentration, etc?
--what's the overall cost/benefit ratio?

There is in fact little data to answer the above questions. The European guidelines currently support the approach of one intravesical chemotherapy instillation immediately following TUR [see:EORTC meta-analysis-Perspectives in bladder cancer on webcafe]

Principles of intravesical therapy: Possible benefits
--high drug concentration is possible
--direct contact is made between tumor and drug
--prolonged contact time
--decreased systemic side effects

The ideal drug should be
--active in eradicating the pre-existing disease and in preventing both recurrence and progression
--the simplest and shortest administration
--no side effects
--reasonable cost

Dose vs activity vs toxicityThere is uncertainty regarding the best dose-activity ratio for intravesical chemo/immunotherapy; Generally the higher the dose, the higher the toxicity for both chemo and immunotherapeutic agents

Early vs. Delayed instillations
A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. Oosterlinck W, Kurth KH, Schroder F, Bultinck J, Hammond B, Sylvester R. Department of Urology, University Hospital, Gent, Belgium. J Urol. 1993 Apr;149(4):749-52. European Organization for Research and Treatment of Cancer Genitourinary GroupPubMedAbstract

Optimal time between instillations- very little data.

One randomized study [Burk, Urologe 1986] compared 3 similar groups:
Group 2: weekly instillatoins for 1 month
Group 2: 2-week interval instill. for 6 months
Group 3: monthly instill. for 1 year
Surprisingly no difference in outcomes were found.

The usefulness of added courses of chemotherapy after treatment failure
40 patients with carcinoma in situ were treated with either Adriamycin or Mitomycin [Solsona, Eur. Urol. 1991]:
Response-52%
Non response-48%
Of the non-responders, 12 of them went on to a second course, of these patients the rate of response was:
Response-57%
No response-43%

Conclusions, What we do know with certainty:No ideal drug exists yet
Optimal conditions for I.V. administration established but not applied
Value of:
Single instillations
Early course
Maintenance Therapy
Additional course
Second line therapy
Intravesical therapy is not strictly necessary

"THE ILLUSION OF KNOWLEDGE IS THE MAJOR OBSTACLE TO THE PROGRESS" Prof. Bassi

Gemcitabine: Deoxycitidine analogue, pyrimidine antimetabolite, that interferes with DNA synthesis via a direct inhibition of ribonucleotide reductase or by means of incorporation of difluorodeoxycitine monophosphate into DNA. As final results GMC inhibits cell growth and trigger apoptosisPemetrexed: Folate analogue, that enter the cell through the reduced folate carrier; undergoes polyglutamation and is retained into the cellEpithilones: Semisynthetic analogues of the natural Epothilones A and B, which have a mode of action similar to taxanes (microtubules stbilization)
Active in both paclitaxel sensitive and refractory tumours; Twice as potent as Paclitaxel in-vitro
Vinflunine: A novel fluorinated Vinca alkaloid

Conclusions 1.:
_GMC and TXNs are highly active in metastatic BC
_Doublets or triplets including GMC and/or TXNs are promising, but have to be compared with standard treatment (GC or M-VAC) in large phase III studies
_Other newer drugs (PEM, Vinflunine, etc) also seem active.

Conclusions 2.:
_ Targeted drugs are marginally active, but the preliminary studies have not been adequately designed
_They need to be evaluated in combination with cytotoxic drugs in patients at least expressing the specific molecular target
_GMC efficacy in SBC is comparable to that of BCG
_Other drugs are in early phase of study in SBC, including differentiating agents and some targeted drugs.
____________________________________________________